Sensors for metal ions and other species involved in biological signaling pathways and other biological functions can provide valuable information regarding the physiological roles of the metal ions and/or species and can serve as a tool in the diagnosis of a variety of pathologies. For example, zinc is a ubiquitous and indispensable element in the human body and the second most abundant d-block metal after iron. Disruptions of zinc homeostasis have been implicated in a number of health disorders such as Alzheimer's disease, diabetes, and certain cancers. However, detailed studies of the molecular mechanisms of intracellular Zn2+ accumulation, trafficking, and function, or mechanisms for other metal ions or biological species, have been limited due to a lack of suitable methods for detection in living biological systems.
Previous methods have involved the irreversible precipitation of metal complexes, which are typically restricted to use in postmortem samples. Fluorescent metal ion sensors have been investigated, but have been limited due to photobleaching and high background signals caused by light scattering. Additionally, as with other optical methods, fluorescence imaging techniques have limited penetration depth and lateral range, making them unsuitable for global analysis of relatively large and opaque specimens, such as live animals.
By contrast, magnetic resonance imaging (MRI) techniques can noninvasively penetrate deep into an intact, opaque object to provide interior 3D information, although its spatial resolution is relatively low compared with that of fluorescence imaging. As one of the most commonly used clinical diagnostic imaging modalities today, MRI is based on a NMR signal arising predominantly from the protons of water molecules. The sensitivity of MRI can be improved by applying contrast agents, which typically comprise paramagnetic metal ions that can influence the NMR relaxation rates of the proton, enhancing the signal in most cases. Factors that determine the relaxivity of a contrast agent include electron spin properties, water molecule accessibility, time scales for molecular motion, and the like. However, for in vivo applications, many MRI techniques have been limited due to insufficient cell membrane permeability. Moreover, some MRI agents comprise toxic metal ions, which have been shown to dissociate from the MRI agent in physiological conditions due to insufficient stability of the metal complex.
Accordingly, improved compositions and methods are needed.